CYCLIN-DEPENDENT KINASES PARTICIPATE IN DEATH OF NEURONS EVOKED BY DNA-DAMAGING AGENTS

Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cell s both in vitro and in vivo. Accordingly, it has become important to u nderstand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important r ole in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and domina nt-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic an d cortical neurons against DNA-damaging conditions. We show that Sindb is virus-induced expression of CKIs p16(ink4), p21(waf/cip1), and p27( kip1), as well as DN-Cdk4 and 6, but not DN-Cdk2. or 3, protect sympat hetic neurons against UV irradiation- and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent cam ptothecin. Finally, in consonance with our hypothesis and these result s, cyclin D1-associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results sugges t that postmitotic neurons may utilize Cdk4 and 6, signals that normal ly control proliferation, to mediate death signaling resulting from DN A-damaging conditions.